Skin cancer is the most common malignancy in the world. One out of three new cancers is a skin cancer. More than 1 million cases of non-melanoma skin cancer (NMSC) (basal cell carcinoma [BCC] and squamous cell cancers [SCC]) occur annually. While the incidence rates for non-melanoma skin cancers continue to rise, there continues to be a substantial impact on morbidity, health and health care costs. The overall goal of this program project (PPG) is to employ novel technologies and develop new therapeutic strategies to eradicate intraepithelial neoplasias in the skin (i.e. actinic keratosis, squamous cell carcinoma in situ) and dramatically reduce the risk of squamous cell carcinoma of the skin. Since the key risk factors and signaling pathways in both melanoma and squamous cell skin cancers, appear linked, these strategies will also be tested for efficacy and safety in preclinical melanoma models. To achieve this goal, we will conduct a multilevel program of rational drug development, including: 1) the identification of the critical molecular targets in solar radiation signaling pathways of SCC and melanoma development; 2) the identification of molecular pathways that contribute to altered terminal differentiation and barrier dysfunction in sun damaged skin involving actinic keratosis (AK) and in situ squamous cell carcinoma (SCIS); 3) the selection of novel chemopreventive agents and synthesis of prodrugs that specifically hit these molecular targets in SCC and melanoma mouse models and definitively interrupt their signaling pathways; 4) the testing of the most promising target-specific agents and prodrugs in preclinical pharmacology and toxicology models required for Investigational New Drug (IND) registrations; and 5) to conduct phase 0, I, Ila and Ilb cancer prevention clinical trials of new IND-registered agents to prove chemopreventive safety, tolerability and efficacy. Knowledge of the key molecular targets in solar ultraviolet radiation signal transduction pathways and the development of multiple topically administered agents that can hit and eradicate these targets ultimately will allow for personalized medical approaches to SCC chemoprevention. A major theme of this PPG fits the scheme of Discovery Development and Delivery. While the three basic science projects continue the aims of identification (discovery) of UV signaling target pathways and agents that modulate these targets, the clinical project will undertake the development process of moving the agents showing efficacy in the SCC and melanoma mouse models into phase 0, 1, 2a and 2b human clinical trials. The delivery step occurs after agents demonstrate efficacy in 2b clinical trials. While this PPG will not take on the task of delivery by running phase III clinical trials, progress of earlier agents discovered and developed previously by the investigators involved in the proposed PPG have resulted in their commercialization, including Melanotan now licensed to the company Cinuvel and myristyl nicotinate(MN) licensed to the company Niadyne. RELEVANCE: Reducing the incidence of these dangerous cancers would not only reduce the potentially severe morbidity and mortality associated with these cancers, but also dramatically reduce the multibillion dollar heath bill associated with surgical and medical treatments required for melanoma and non-melanoma skin cancers.